Histamines are implicated in a number of medical conditions, including inflammation, asthma, allergy, atopic dermatitis, stroke, myocardial infection, migraine, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and psoriasis. Histamines regulate the intensity and duration of immune responses and are involved in cell-to-cell communication. Histamines are also involved in leukocyte migration and bronchovasoconstriction. As established by radioligand binding, physiological assays, and molecular cloning, different types of receptors for histamines exist. Furthermore, specific histamine receptor subtypes are involved in specific medical conditions such that drugs with subtype selectivity can be utilized to target individual medical conditions.
At present there are four known human histamine receptors, H1, H2, H3 and H4, all of which are G-protein coupled molecules. Although the existence of histamine receptors had been established pharmacologically for decades, the H1 and H2 receptors were cloned only in 1991 (Yamashita et al. 1991 Proc. Natl. Acad. Sci. USA 88:11515; Gantz et al. 1991 Proc. Natl. Acad. Sci. USA 88:429), and the H3 receptor and the H4 receptor were not cloned until more recently (Lovenberg et al. 1999 J. Mol. Pharmacol. 55:1101; U.S. Pat. No. 6,136,559; WO 00/20011 (PCT/US98/21090); Oda et al. 2000 J. Biol. Chem. 275:36781; Zhu et al. 2001 Mol. Pharmacol. 59:434; Liu et al. 2001 Mol. Pharmacol. 59:420; Morse et al. 2001 J. Pharm. Exp. Ther. 296:1058; as well as U.S. Pat. No. 6,204,017 and WO 01/25432 A2 (PCT/US00/27481); WO 01/46414 A1 (PCT/JP00/09038); and Nguyen et al. 2001 Mol. Pharmacol. 59:427).
The H3 receptor subtype has been found in both the central nervous system and in the peripheral nervous system as a presynaptic receptor controlling the release of histamine and of several neurotransmitters. The CNS effect of the H3 antagonists makes them potential candidates for the treatment of obesity, epilepsy, depression, sleep/wake disorders and age-related memory disorders, such as Alzheimer's disease and attention-deficit hyperactivity disorders. The negative feedback mechanism on sensory C fibres and the resultant anti-inflammatory effects of H3 receptor agonists suggests a possible role for these compounds in treatment of migraine, asthma, cardiac disorders and neurogenic airway inflammation. Various antagonists of the H3 histamine receptor and methods for their use for treating CNS disorders, including Alzheimer's disease, narcolepsy, and comas induced by stroke, drugs or alcohol, for suppressing appetite in the treatment of obesity, and for treatment of allergy, inflammation, cardio and cerebro vascular diseases, gastrointestinal disorders, psychiatric disorders, sleep disorders and hypothalnic dysfunction are disclosed in U.S. Pat. Nos. 5,380,858; 5,486,526; 5,633,382; 5,639,775; 5,652,258; 5,990,317; 6,008,240; 6,072,057; and 6,166,060; see also U.S. Pat. No. 6,136,559; WO 00/20011 (PCT/US98/21090).
Recent molecular studies have shown that a single form of the H3 gene can give rise to multiple mRNA isoforms in rat (Drutel et al. 2001 Mol. Pharmacol. 59:1) and in guinea pig (Tardival-Lacombe et al. 2000 Neuroreport 11:755). In humans, six splice variants of the H3 receptor were recently reported in the thalamus (Coge et al. Biochem. J. 2001 355:279). These variants were found to be coexpressed in human brain, but their relative distribution varied in a region-specific manner. The variants displayed deletions in either the putative second transmembrane domain or in the third intracellular loop.
In view of the important role that histamines play in many physiological processes and medical conditions, there is a need for materials and methods, including novel histamine receptors, useful for the identification of agonists, inverse agonists and antagonists selective for specific types of histamine receptors.